BIOLOGICS & BIOMARKERS:

EMERGING APPROACHES TO

EFFECTIVE ASTHMA

TREATMENTS Todd A. Mahr, MD, FACAAI, FAAAAI, FAAP

Allergy, Asthma & Immunology

Gundersen Health System

La Crosse, WI

Adjunct Clinical Professor Of Pediatrics

University of Wisconsin School of Medicine and Public Health

Disclosures

• Speaker/Advisory/Honorarium/Research

– AstraZeneca, Circassia, Genentech, MEDA, Merck, Mylan, Teva, Kaleo, Pfizer

• Thank you to Dr. Jared Darveaux for slides

Objectives

• Discuss different biomarkers used to identify specific asthma endotypes

• Discuss how to use biomarkers to personalize asthma care with current

medications

• Discuss current biologics and those being developed to target specific asthma

endotypes

Background

• Asthma is a heterogeneous disease associated

with significant impairment and risk

• Therapeutic responses that is highly variable

• Current treatments are usually effective for patients with mild to moderate

disease

• Patients with more severe asthma are often unresponsive to medication

• “One size fits all” approach often unsuccessful

Current Guidelines

1. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. 2007

Inhaler Technique

• https://www.youtube.com/watch?v=bDHEEV0M62Y

Background

• As we learn more about the mechanisms involved asthmatic airway

inflammation, several key components have been identified

• These can offer potential therapeutic targets

• However, the inflammatory process is complex, interactive, and redundant

• Variable between patients

• How do we decide who is going to respond to different

therapeutic agents?

Biomarkers in General

• Traceable substances used to examine organ function or

other aspects of health1

• HgbA1c in diabetes

• CD4 T-cell count for AIDS patients

• Troponins in MI

• At their best, biomarkers are used to determine presence

or absence of disease, disease severity and progression,

targets for therapy and response to therapy, and guidance

about the affected subject’s survival

1. Lapraz JC. Glob Adv Health Med 2013

Biomarkers in Asthma

• Spirometry – diagnosis, severity, response to treatment

• Do not tell us about underlying cause of disease

• Several biomarkers have been identified that can help define asthma

endotypes

• To be most useful, biomarkers in asthma must1

• Be vetted in large numbers of patients

• Be able to be measured by standard methods to ensure widespread and accurate use

• Display strong sensitivity, specificity, accuracy and reproducibility.

1. Berry A. J Allergy Clin Immunol 2016

Lotvall J. J Allergy Clin Immunol 2011

E

Muraro A, et. al. J Allergy Clin Immunol 2016;137(5):1347-58

Muraro A, et. al. J Allergy Clin Immunol 2016;137(5):1347-58

IgE as a Biomarker

• Allergic sensitization is present in the majority of

asthmatic patients1

• Allergy is known to contribute to asthmatic inflammation

• Activated mast cells release histamine and produce prostaglandins,

leukotrienes, and cytokines2

• IgE levels correlate with asthma severity in both children

and adults3

• This made IgE a natural target for

asthma therapy

1. Darveaux J. JACI, In practice 2015

2. Fahy JV. Am J Respir Crit Care Med 1997

3. Burrows B. Am J Respir Crit Care Med 1995

Omalizumab

• Monoclonal antibody targeted at the Fc portion of IgE

• Prevents IgE from binding to its receptor

• Reduces symptoms, prevent exacerbations, allowed for a reduction in ICS use without a loss of asthma control

• Omalizumab is approved for use ages 6 and above

• Requires sensitization to a perennial allergen and sufficient IgE

level

• Dose/frequency of administration is based on weight and IgE level

Omalizumab

Busse W, N Engl J Med 2011

• Omalizumab reduced:

• Mean number of days during

which participants had symptoms

by 24.5% (from 1.96 to 1.48;

p<0.001)

• Exacerbations by 18.5 % (48.8%

in the placebo group vs. 30.3% in

the omalizumab group; p<0.001)

• Inhaled Glucocorticoid dose by

109 mcg/day (p<0.001)

Efficacy of Omalizumab

Efficacy of Omalizumab

Busse WW, et al. N Engl J Med. 2011

Choosing the Right Biomarker

Hanania NA, et. al. Am. J. Respir. Crit. Care Med. 2013

Eosinophils

• Lung histology in asthmatic patients is often characterized by eosinophilic

infiltration

• Boost the allergic response

• Recruit inflammatory cells

• Promote IgE production through secretion of other interleukins

• Can be elevated both peripherally and in sputum

• Blood eosinophilia seems to be the best marker to identify sputum eosinophilia

• Reductions in eosinophils linked to clinical improvement

• Berry A. J Allergy Clin Immunol 2016

• Seys SF. Curr Opin Pulm Med 2016

• Brusselle, G.G. Nat. Med. 2013

• Jacobsen, E.A. J Allergy Clin Immunol. 2007

• Gleich, G.J. Annu Rev Med. 1993

• Miranda C. . J Allergy Clin Immunol. 2004

Eosinophils

Green, R.H. Lancet, 2002

Varricchi G, et.al. Curr Opin Allergy Clin Immunol 2016;16(2):186-200

Targeting Eosinophils

• Early studies with anti-IL5 therapy were disappointing

• Studied in moderate to severe asthmatics

• Reductions in sputum and peripheral eosinophil counts were seen, but no effects on clinical

features of asthma

• Later studies requiring peripheral eosinophilia as inclusion criteria were much

more successful

• Highlights the need to select appropriate patients based on biomarkers, in this

case peripheral eosinophils

Effect of Targeting Eosinophils • Consistent feature of medications targeting eosinophils is reduction in exacerbations

• Atopic status has no impact on response to mepolizumab

• Most impressive responses are in patients with high peripheral eosinophilia

Haldar, et al. N Engl J Med 2009

Darveaux J. JACI, In Practice 2015

Effect of Targeting Eosinophils • Consistent feature of medications targeting eosinophils is reduction in exacerbations

• Atopic status has no impact on response to mepolizumab

• Most impressive responses are in patients with high peripheral eosinophilia

Haldar, et al. N Engl J Med 2009

Darveaux J. JACI, In Practice 2015

Fractional Exhaled Nitric Oxide - FENO

• Nitric Oxide is produced by respiratory epithelium • Increased with allergic

type inflammation

• Highly correlates with sputum eosinophilia

• Like eosinophils, high levels correlate with increased risk of exacerbation

FENO

• Although eNO levels

correlate with

eosinophilia, these are

thought to be 2

separate biomarkers

• Patients treated with

mepolizumab have

reductions in eosinophils

without change in eNO

Haldar P, et al. N Engl J Med. 2009

FENO

• Patients with high eNO are

likely to benefit from ICS

• Upper limit of normal is 25 ppb

• High eNO despite ICS therapy

may reflect a subtype

unresponsive to ICS

• Levels rise quickly once

ICS is stopped, so can be

used to monitor adherence

IL-4 and IL-13

IL-4 and IL-13

• IL-4 and IL-13 work in

concert and produces

many of the same effects

• Two receptor types

• One binds IL-4 alone, the

other binds both IL-4 and

IL-13

IL4 & IL13 Targeted Therapies

• Approaches to reduce IL-4 activity have included

• Anti-IL-4 antibody

• Soluble IL-4 receptor

• IL-4 transcription inhibitors

• IL-4/IL-13 receptor antagonists

• These have met mixed results as far as efficacy in

asthma

• The overlapping actions of these cytokines brings into

question the potential effectiveness of blocking of either

of them individually.

Periostin

• Extracellular matrix protein

produced by epithelial cells

• Induced by IL-13

• High periostin levels are

thought to reflect a high Th2

endotype

• Periostin has effects on

epithelial cell function and

effects on fibroblasts

• May contribute to the

mechanisms of airway

remodeling in asthma

Utilizing Periostin

• Lebrikizumab is an anti-IL-13

monoclonal antibody

• Improved FEV-1 in asthmatics, but

showed a greater improvement in

“high Th2” patients

Corren J, et al. N Engl J Med. 2011

IL4 & IL13 Targeted Therapies

• Dupilumab – IL4R

blocker

• Inhibits interaction

with BOTH IL-4

and IL-13

Wenzel S, et al. N Engl J Med. 2013

IL4 & IL13 Targeted Therapies

• Dupilumab – IL4R

blocker

• Inhibits interaction

with BOTH IL-4

and IL-13

Wenzel S, et al. N Engl J Med. 2013

IL4 & IL13 Targeted Therapies

• Dupilumab – IL4R

blocker

• Inhibits interaction

with BOTH IL-4

and IL-13

Wenzel S, et al. N Engl J Med. 2013

IL4 & IL13 Targeted Therapies

• Dupilumab – IL4R

blocker

• Inhibits interaction

with BOTH IL-4

and IL-13

Wenzel S, et al. N Engl J Med. 2013

IL4 & IL13 Targeted Therapies

• Dupilumab – IL4R

blocker

• Inhibits interaction

with BOTH IL-4

and IL-13

Wenzel S, et al. N Engl J Med. 2013

Unmet Needs

• Although much has been learned about the pathophysiologic mechanisms

involved in different asthma endotypes, practical application of biomarkers in

clinical practice is still being developed

• Invasiveness of tests, accessibility, cost

• The vast majority or research has been directed at T2 predominant asthma

phenotypes

• Other phenotypes, specifically T2 low or neutrophilic asthma do not typically respond to

either standard therapy or current biologics

• Further research is needed to identify biomarkers and potential therapeutic agents for this

phenotype

Who should see a specialist?

• Current recommendations are that any patient requiring Step 4 treatment or

higher should be evaluated by an asthma specialist

• Step 4 = Medium dose ICS + LABA

Summary

• A significant portion of asthmatics do not achieve control with current inhaler

treatments

• Several biologic agents have been developed, and others are currently being

explored targeting key components of asthma pathophysiology

• Biomarkers can help provide information to strategically select biologic agents

for specific asthma endotypes

personalized therapy